Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis.

BACKGROUND: Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS: Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS: Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS: Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Human epididymis protein 4 as a new diagnostic biomarker for rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: This study aimed to evaluate the role of human epididymis protein 4 (HE4) in the diagnosis and determination of the severity of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: HE4 levels in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) samples were determined via electrochemiluminescence immunoassays in 102 RA patients (46 patients with ILD and 56 patients without ILD) and 51 healthy controls (HCs). RESULTS: Serum HE4 levels were significantly higher in RA-ILD patients (141.8±65.92 pmol/l) than those in the RA-no ILD patients (82.67±26.17 pmol/l) and healthy controls (35.72±7.6 pmol/l) (p<0.0001). Consistent with serum HE4 levels, BALF HE4 levels were significantly higher in RA-ILD patients (637.6±154.9 pmol/l) than those in the RA-no ILD patients (427.3±111.2 pmol/l) and healthy controls (206.9±30.46 pmol/l) (p<0.0001). In RA-ILD patients, HE4 levels were positively correlated with HRCT (high-resolution computed tomography) fibrosis scores, whereas a significant inverse relationship was found between HE4 levels and lung function parameters (such as, diffusion capacity of the lung for carbon monoxide (DLCO)). The logistic regression analysis showed that high levels of BALF HE4 (≥595 pmol/l) were associated with RA-ILD (odds ratio [OR] =8.09; 95% confidence interval [CI] =1.317-49.682; p=0.024). CONCLUSIONS: Serum and BALF HE4 levels were elevated in RA-ILD patients and strongly associated with the severity of ILD, thus supporting their potential clinical value as a new diagnostic aid for patients with RA-ILD.

Factors associated with mortality in rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Interstitial lung disease (ILD) is a common and potentially life-threatening complication for rheumatoid arthritis (RA) patients. However, there is a lack of clear prognostic factors in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. The purpose of this study was to complete a systematic review and meta-analysis of the factors associated with mortality in RA-ILD patients. METHODS: Medline, EMBASE and the Cochrane Library were searched up to September 1, 2020. The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, pooled hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) and pooled risk ratios (RRs) with 95% CIs were calculated to assess the factors associated with mortality in RA-ILD. RESULTS: Twenty-three of 3463 articles were eligible, and ten factors associated with mortality for RA-ILD were evaluated in the meta-analysis. Older age (HRs = 1.04, 95% CI 1.03-1.05), male sex (HRs = 1.44, 95% CI 1.21-1.73), having a smoking history (HRs = 1.42, 95% CI 1.03-1.96), lower diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (HRs = 0.98, 95% CI 0.97-1.00), forced vital capacity (FVC)% predicted (HRs = 0.99, 95% CI 0.98-1.00), composite physiological index (CPI) (HRs = 1.04, 95% CI 1.02-1.06), usual interstitial pneumonia (UIP) pattern on HRCT (HRs = 1.88, 95% CI 1.14-3.10 and RRs = 1.90, 95% CI 1.50-2.39), emphysema presence (HRs = 2.31, 95% CI 1.58-3.39), and acute exacerbation of ILD (HRs = 2.70, 95% CI 1.67-4.36) were associated with increased mortality in RA-ILD, whereas rheumatoid factor (RF) positive status was not associated. CONCLUSIONS: Through this systematic review and meta-analysis, we found that older age, male sex, smoking history, higher CPI, lower DLCO% predicted, lower FVC% predicted, UIP pattern on HRCT, emphysema presence and acute exacerbation of ILD were associated with an increased risk of mortality in RA-ILD.

Prevalence and risk factors of systemic sclerosis-associated interstitial lung disease in East Asia: A systematic review and meta-analysis.

OBJECTIVE: Interstitial lung disease (ILD) is a common and potentially life-threatening complication for individuals with systemic sclerosis (SSc). The purpose of this study was to complete a systematic review and meta-analysis on prevalence and risk factors of SSc-ILD in East Asia. METHODS: Medline, EMBASE, and Cochrane Library were searched up to January 22, 2021. The Reporting of Observational Studies in Epidemiology (STROBE) statement was applied to access the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, we calculated the pooled prevalence, weighted mean differences (WMDs), pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs), and performed subgroup analysis, sensitivity analysis, and publication bias with Egger's test. RESULTS: Twenty-seven of 1584 articles were eligible and a total of 5250 patients with SSc were selected in the meta-analysis. The pooled prevalence of SSc-ILD in East Asia was 56% (95% CI 49%-63%). The SSc-ILD prevalence was higher in China (72%) than in Japan (46%) and Korea (51%). Longer disease duration (WMD = 1.97, 95% CI 0.55-3.38), diffuse SSc (OR = 2.84, 95% CI 1.91-4.21), positive anti-topoisomerase I antibody (ATA) (OR = 4.92, 95% CI 2.74-8.84), positive anti-centromere body antibody (ACA) (OR = 0.14, 95% CI 0.08-0.25), positive anti-U3 ribonucleoprotein (RNP) antibody (OR = 0.17, 95% CI 0.04-0.66), and higher erythrocyte sedimentation rate (ESR) (WMD = 6.62, 95% CI 1.19-12.05) were associated with SSc-ILD in East Asia. CONCLUSION: Through this systematic review and meta-analysis, we found that ILD occurs in up to approximately 56% of patients with SSc in East Asia. Longer disease duration, diffuse SSc, positive ATA, negative ACA, negative anti-U3 RNP antibody, and higher ESR were risk factors for SSc-ILD.

Intergenotype recombinant analysis of full-length hepatitis B virus genomes from 516 Chinese patients with different illness categories.

This study aimed to reveal characteristics and clinical relevance of HBV intergenotypic recombinants. Serum samples of 516 patients from Northern China were collected, including 131 with acute hepatitis B (AHB), 239 with chronic hepatitis B (CHB), and 146 with acute-on-chronic liver failure (ACLF). Full-length HBV genomes were sequenced and HBV genotypes were analyzed. Genotypes C, B, D, and intergenotypic recombinants were detected in 71.12% (367/516), 19.96% (103/516), 0.78% (4/516), and 8.14% (42/516) of the patients. The latter comprised 21 with AHB, 10 with CHB, and 11 with ACLF; and the occupations of intergenotypic recombinants in AHB, CHB, and ACLF groups were 16.03%, 4.18%, and 7.53% (P < 0.01), respectively. HBV B/C and C/D hybrids accounted for 85.71% (36/42) and 14.29% (6/42) of the intergenotypic recombinants. In AHB and CHB groups, serum HBV DNA levels were significantly lower in patients with intergenotypic recombinants than those without intergenotypic recombinants. Difference in basal core promoter A1762T/G1764A mutations and precore G1896A mutation incidences was not significant between B/C recombinant and genotypes B or C virus, although the significance was there between genotypes B and C viruses. Clonal sequence analysis showed that intergenotypic recombinant viral strains existed in single or in concomitance with other genotype virus. Phenotypic analysis showed that viral replication capacity was similar between recombinant and non-recombinant strains in tested samples. Taken together, the occurrence of intergenotypic recombinant HBV is relatively low in HBV-infected patients in Northern China, and intergenotypic recombinant HBV infection is likely favorable to induce an acute course of disease. J. Med. Virol. 89:139-145, 2017. © 2016 Wiley Periodicals, Inc.

Association between hepatitis B virus basal core promoter/precore region mutations and the risk of hepatitis B-related acute-on-chronic liver failure in the Chinese population: an updated meta-analysis.

BACKGROUND: The relationship between hepatitis B virus (HBV) mutations in basal core promoter (BCP) and precore (PC) regions and the risk of hepatitis B-related acute-on-chronic liver failure (HB-ACLF) remains uncertain. METHODS: Databases were searched for papers that were published in English or Chinese until April 31, 2015. The odds ratios (ORs) of HBV mutation were pooled by using a fixed or random-effects model according to heterogeneity. RESULTS: Data for 13 studies with a total of 1,149 HB-ACLF and 1,867 chronic hepatitis B (CHB) cases were retrieved. Statistically significant summary ORs for HB-ACLF were obtained for T1753V (1.99; 95 % confidence interval 1.30-3.02) and A1762T/G1764A (2.11; 95 %, 1.75-2.54) in the BCP region and for A1846T (3.33; 95 %, 2.23-4.97), G1896A (2.78; 95 %, 2.07-3.74), and G1899A (3.09; 95 %, 1.82-5.25) in the PC region. In subgroup analysis, BCP mutations were found to have higher ORs in age-matched studies, but PC mutations were found to have higher ORs in age-unmatched studies; patients with the mutations in HBV genotype C were more susceptible to HB-ACLF; patients with pre-existing liver cirrhosis had a higher risk of HB-ACLF occurrence. In sensitivity, specificity, and accuracy analysis, A1762T/G1764A had the highest sensitivity (67.43 %); A1762T/G1764A + G1896A triple mutations had the highest specificity (93.70 %); and T1753V + A1762T + G1764A mutation had the highest accuracy (65.42 %). CONCLUSIONS: HBV T1753V, A1762T/G1764A, A1846T, G1896A, and G1899A mutations are correlated with an increase in the risk of HB-ACLF. These mutations alone and in combination may be predictive of the susceptibility of patients with CHB to developing HB-ACLF.